Wnt5a (wingless-related MMTV integration site 5a) is a member of a large family of cysteine-rich growth factors. Proteins in this family are highly conserved and naturally secreted; upon secretion, they provide signals that regulate cell-cell interactions during embryogenesis. More specifically, the Wnt proteins seem to be critical for pattern formation, cell fate determination, and other events required for proper embryonic development. Researchers have studied the mechanisms by which Wnt proteins function in several different ways. They have, for example, performed genetic studies in Drosophila and Caenorhabditis elegans and biochemical assays in cell culture. They have also altered gene expression in Xenopus embryos and found that mutated Wnt-encoding genes in the mouse lead to specific developmental defects.
On a cellular level, Wnt5a binds to members of the Frizzled (Fzd) family of seven-transmembrane domain receptors on the cell surface, and this triggers a series of intracellular events that ultimately regulate gene transcription. These intracellular events are grouped according to two known signaling pathways, the canonical Wnt/β-catenin pathway (He et al., Science 275:652-654, 1997; Toyofuku et al., J. Cell Biol. 150:225-41, 2000; Kawakami et al., Cell 104:891-900, 2001) and the Wnt/Ca++ pathway (Slusarski et al., Dev. Biol. 182:114-120, 1997; Kuhl et al., J. Biol. Chem. 275:12701-12711, 2000; and Kuhl et al., Mech. Dev. 106:61-76, 2001) (FIG. 1). Wnt5a-mediated release of intracellular Ca++ leads to the phosphorylation of both protein kinase C (PKC) and calcium/calmodulin dependent protein kinase II (CamK II), and the activation of these two kinases blocks the Wnt/β-catenin signaling cascade via phosphorylation of dishevelled (dvl) (by PKC) or Lymphoid Enhancer-binding Factor (LEF-1) (by CamK II). These distinct Wnt signaling cascades control convergent extension movements in Xenopus, and Wnt5a has been shown to regulate the expression of β-catenin responsive genes in this system (Kuhl et al., Mech. Dev. 106:61-76, 2001). The signaling pathway that is induced may be governed by the cell surface Fzd receptor to which Wnt5a binds (Holmen et al., J. Biol. Chem. (in press), 2002).
Wnt genes and Wnt signaling have been studied in the context of cellular proliferation, but the role of Wnt5a in tumor development is still unclear. Unlike members of the Wnt1 class of transforming Wnt genes, transfection with Wnt5a fails to transform C57MG cells, an epithelial cell line derived from normal mouse mammary tissue (Willert et al., BMC Dev. Biol. 2:8, 2002), and ectopic expression of human Wnt5a in a transformed uroepithelial cell line inhibited growth (Olson et al., Cell Growth Differ. 8:417-23, 1997). However, addition of Wnt5a to the media of cultured cells has also been reported to stimulate hematopoietic stem cell proliferation including lymphoid and myeloid progenitors (Van Den Berg, et al., Blood 92:3189-202, 1998; Austin, et al., Blood 89:3624-3635, 1997). Upregulation of WNT5a has been observed in various human cancers (Lejeune et al., Clin. Cancer Res. 1:215-222, 1995; Tozzo et al., Cancer Res. 55:3495-3499, 1995) and WNT5a has recently been reported to facilitate cell invasion in human metastatic melanoma (Weeraratna et al., Cancer Cell 1:279-88, 2002).